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Kras is frequently mutated in lung cancer and two isoforms are generated via alternative splicing. Here, the authors show that the two isoforms have divergent roles in cancer stem cells and the main tumour cell population, which are regulated by hypoxia and endoplasmic reticulum stress.

Abstract Alzheimer’s disease (AD) affects millions of people worldwide and represents the most prevalent form of dementia. Treatment strategies aiming to interfere with the formation of amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs), the two major AD hallmarks, have shown modest or no effect. Recent evidence suggests that ferroptosis, a type of programmed cell death caused by iron accumulation and lipid peroxidation, contributes to AD pathogenesis. The existing link between ferroptosis and AD has been largely based on cell culture and animal studies, while evidence from human brain tissue is limited. Here we evaluate if Aβ is associated with ferroptosis pathways in post-mortem human brain tissue and whether ferroptosis inhibition could attenuate Aβ-related effects in human brain organoids. Performing positive pixel density scoring on immunohistochemically stained post-mortem Brodmann Area 17 sections revealed that the progression of AD pathology was accompanied by decreased expression of nuclear receptor co-activator 4 and glutathione peroxidase 4 in the grey matter. Differentiating between white and grey matter, allowed for a more precise understanding of the disease’s impact on different brain regions. In addition, ferroptosis inhibition prevented Aβ pathology, decreased lipid peroxidation and restored iron storage in human AD iPSCs-derived brain cortical organoids at day 50 of differentiation. Differential gene expression analysis of RNAseq of AD organoids compared to isogenic controls indicated activation of the ferroptotic pathway. This was also supported by results from untargeted proteomic analysis revealing significant changes between AD and isogenic brain organoids. Determining the causality between the development of Aβ plaques and the deregulation of molecular pathways involved in ferroptosis is crucial for developing potential therapeutic interventions.

Background: Receiving hemodialysis treatment makes end-stage renal disease (ESRD) patients highly vulnerable amidst the COVID-19 pandemic. Hence, their kidney disease quality of life (KDQOL) is affected. We aimed to examine the association between fear of COVID-19 (FCoV-19) and KDQOL, and the effect modification of Health literacy (HL) on this association.Material and Methods: A survey was conducted at 8 hospitals from July 2020 to March 2021 on 972 patients. Data collection includes socio-demographic factors, clinical parameters, HL, digital healthy diet literacy (DDL), hemodialysis diet knowledge (HDK), FCoV-19, suspected COVID-19 symptoms (S-COVID-19-S), and KDQOL.Results: Higher HL scores B = 0.13 (95% CI = 0.06–0.21, p = 0.001) and HDK scores B = 0.58 (95% CI = 0.31–0.85, p = 0.001) were associated with higher KDQOL scores. Whereas, S-COVID-19-S B = −6.12 (95% CI = −7.66 to – 4.58, p = 0.001) and FCoV-19 B = −0.91 (95% CI = −1.03 to – 0.80, p = 0.001) were associated with lower KDQOL scores. Notably, higher HL scores significantly attenuate the negative impact of FCoV-19 on overall KDQOL and the kidney disease component summary.Conclusions: In hemodialysis patients, FCoV-19 and S-COVID-19-S were associated with a lower KDQOL. Health literacy significantly mitigates the negative impact of FCoV-19 on KDQOL. Strategic public health interventions to improve HL are suggested to protect patient’s KDQOL during the pandemic.

Spatially explicit biogeographic models are among the most used methods in conservation biogeography, with correlative species distribution models (SDMs) being the most popular among them. SDMs can identify the potential for species’ and community range shifts under climate change, and thus can inspire, inform, and guide complex and adaptive conservation management planning efforts such as collaborative transboundary conservation frameworks. However, SDMs are rarely developed collaboratively, which would be ideal for conservation applications of such models. Further, SDMs that are applied to conservation often do not follow best practices of the field, which are particularly important for applications in climate change contexts for which model extrapolation into potentially novel climates is necessary. Thus, while there is substantial promise, particularly among machine-learning based SDM approaches, there are also many pitfalls to consider when applying SDMs to conservation, and especially in the context of transboundary management under climate change. Here, we summarize these pitfalls and the key steps to mitigate them and maximize the promise of applying SDMs to facilitate transboundary conservation planning under climate change. We argue that conservation modeling capacity must be elevated among practitioners such that they can easily implement best practices when using SDMs, especially regarding: 1) avoiding model overcomplexity, 2) addressing input data bias, and 3) accounting for uncertainty in model extrapolations and projections. While our discussion centers mainly on the pitfalls and opportunities of applying the most popular correlative SDM algorithm, Maxent, our suggestions can also be generalized to a range of other SDM tools. Overall, improved training in, tools for, and implementation of best practices in biogeographic models such as SDMs hold great promise to facilitate and help guide complex, transboundary collaborations for long-term planning of conservation under climate change.

Ecological niche models (ENMs) can project changes in species’ distributions under climate change and thus inform conservation efforts and further our understanding of patterns of change. Predictions of species’ distribution shifts under climate change in topographically and geologically complex landscapes, such as karst landforms, should be improved by better integration of non-climate abiotic variables, such as karst geology or habitat structure, into model projections. We built ENMs for one of the limestone langurs, a group of leaf monkeys adapted to forests on the Sino-Vietnamese limestone karst landform. We collected occurrence localities for François’ leaf monkeys (Trachypithecus francoisi) and thinned them to avoid sampling bias. We included as environmental parameters a global dataset for karst geology and 19 bioclimatic variables derived from monthly temperature and precipitation at 30 arc-second resolution. ENMs including karst geology and climatic variables outperformed and differed spatially from climate-only models. Across six future-climate scenario projections, the optimal karst+climate model differed from the best climate-only model and predicted more spatial overlap with karst in the future, a contraction in total area of suitable habitat by the 2070s, and a small loss in the amount of suitable habitat in existing conservation areas. This study shows the importance of considering other abiotic factors beyond climate in projections of suitable habitat under climate change for species in complex landscapes. Because our results show that karst and climate interact to explain the distribution of a karst-adapted species, the results also suggest that, under climate change, these interactions are likely to produce altered networks of species into novel biological communities. Finally, our results support the need for conservation of limestone habitats and cross-border collaboration to maintain refuges and movement connectivity for endangered species in the face of climate change.

Indochina is known as one of the world’s biodiversity hotspots, with populations of many endangered and/or endemic species dramatically declining due to a range of threats, such as illegal hunting, habitat destruction, and global climate change. Climate change is expected to alter the region’s habitat and ecosystem conditions, force contraction of species ranges, and increase the likelihood of local extinctions. Maxent is a widely used modelling approach to predict the species’ current potential distribution, project range shifts in response to climate change, and inform conservation planning. Here, we collated known records and built models for both present and future climatically suitable habitat of the Owston’s Civet (Chrotogale owstoni), an endangered and poorly studied small carnivore occurring in Vietnam, eastern Laos, and a small part of southern China. Projections of climatically suitable habitat for the civet in most climate change scenarios and timeframes suggest significant habitat loss and fragmentation within its current range as a consequence of upward contraction. We recommend that future conservation efforts for C. owstoni focus on key refugia spreading along the Annamite Range in the border area between Vietnam and Laos. To mitigate climate-related extinction risk, close cooperation between Vietnam and Laos’ governmental agencies, research institutions, and non-governmental conservation organizations will play an important role in conserving the remaining habitat of this endangered species.

The commonly mutated human KRAS oncogene encodes two distinct KRAS4A and KRAS4B proteins generated by differential splicing. We demonstrate here that coordinated regulation of both isoforms through control of splicing is essential for development of Kras mutant tumors. The minor KRAS4A isoform is enriched in cancer stem-like cells, where it responds to hypoxia, while the major KRAS4B is induced by ER stress. KRAS4A splicing is controlled by the DCAF15/RBM39 pathway, and deletion of KRAS4A or pharmacological inhibition of RBM39 using Indisulam leads to inhibition of cancer stem cells. Our data identify existing clinical drugs that target KRAS4A splicing, and suggest that levels of the minor KRAS4A isoform in human tumors can be a biomarker of sensitivity to some existing cancer therapeutics.

Ecological niche models (ENMs) can project changes in species’ distributions under climate change and thus inform conservation efforts and further our understanding of patterns of change. Predictions of species’ distribution shifts under climate change in topographically and geologically complex landscapes, such as karst landforms, should be improved by better integration of non-climate abiotic variables, such as karst geology or habitat structure, into model projections. We built ENMs for one of the limestone langurs, a group of leaf monkeys adapted to forests on the Sino-Vietnamese limestone karst landform. We collected occurrence localities for François’ leaf monkeys (Trachypithecus francoisi) and thinned them to avoid sampling bias. We included as environmental parameters a global dataset for karst geology and 19 bioclimatic variables derived from monthly temperature and precipitation at 30 arc-second resolution. ENMs including karst geology and climatic variables outperformed and differed spatially from climate-only models. Across six future-climate scenario projections, the optimal karst+climate model differed from the best climate-only model and predicted more spatial overlap with karst in the future, a contraction in total area of suitable habitat by the 2070s, and a small loss in the amount of suitable habitat in existing conservation areas. This study shows the importance of considering other abiotic factors beyond climate in projections of suitable habitat under climate change for species in complex landscapes. Because our results show that karst and climate interact to explain the distribution of a karst-adapted species, the results also suggest that, under climate change, these interactions are likely to produce altered networks of species into novel biological communities. Finally, our results support the need for conservation of limestone habitats and cross-border collaboration to maintain refuges and movement connectivity for endangered species in the face of climate change.

Carrier mobility in doped conjugated polymers is limited by Coulomb interactions with dopant counterions. This complicates studying the effect of the dopant's oxidation potential on carrier generation because different dopants have different Coulomb interactions with polarons on the polymer backbone. Here, dodecaborane (DDB)-based dopants are used, which electrostatically shield counterions from carriers and have tunable redox potentials at constant size and shape. DDB dopants produce mobile carriers due to spatial separation of the counterion, and those with greater energetic offsets produce more carriers. Neutron reflectometry indicates that dopant infiltration into conjugated polymer films is redox-potential-driven. Remarkably, X-ray scattering shows that despite their large 2-nm size, DDBs intercalate into the crystalline polymer lamellae like small molecules, indicating that this is the preferred location for dopants of any size. These findings elucidate why doping conjugated polymers usually produces integer, rather than partial charge transfer: dopant counterions effectively intercalate into the lamellae, far from the polarons on the polymer backbone. Finally, it is shown that the IR spectrum provides a simple way to determine polaron mobility. Overall, higher oxidation potentials lead to higher doping efficiencies, with values reaching 100% for driving forces sufficient to dope poorly crystalline regions of the film.

Background: Determining the clinical and subclinical characteristics related to the recurrence status in patients with a thyroid carcinoma has great significance for prognosis, prediction of recurrence and monitoring of treatment outcomes. This study aimed to determine the association between recurrence rate and some characteristics in patients with thyroid carcinoma. Patients and Methods: The study was conducted by descriptive method with longitudinal follow-up on 102 thyroid carcinoma patients at 103 Military Hospital, Hanoi, Vietnam, from July 2013 to December 2016. Results: Univariate analysis showed that there was a relationship between the recurrence characteristics in the studied patients and the characteristics of lymph node metastasis (P = 0.026; OR = 15; 95% CI = 1.4–163.2) and BRAF V600E mutation status (P = 0.01; OR = 3.41; 95% CI = 1.31–8.88). When analysing the multivariable Logistic regression model, there was a positive correlation between the occurrence of BRAF V600E gene mutation (P = 0.032; OR = 17.649; 95% CI = 1.290–241.523) and male sex (P = 0.036; OR = 12.788; 95% CI = 1.185–137.961) and the occurrence of recurrence in study patients. The mean time to relapse was earlier in male patients than in female patients (P = 0.02). The mean time to relapse in patients with the BRAF V600E mutation (31.81 ± 1.14 months) was shorter than the mean time to relapse in the group without the mutation (57.82 ± 2.08 months) (P = 0.01). The group of patients with mutations in the BRAF V600E gene increased the risk of recurrence compared with the group without the mutation (HR = 9.14, P = 0.04). Conclusion: There is a positive correlation between recurrence and masculinity, lymph node metastasis and the occurrence of BRAF V600E mutations in thyroid carcinoma patients.

BaTiO3 thin films with different annealing times were grown on LSMO/STO (001) substrates by pulsed laser deposition. An interesting phenomenon of loss-and-reappearance of the interfacial layer in BaTiO3 was detected in the x-ray diffraction results, and the ordered–unordered–ordered lattice transformation caused by oxygen vacancies’ filling was thought to be the reason. The ferroelectric domain was also confirmed to form during such an annealing process according to the piezoresponse force microscopy, transmission electron microscopy, and phase-field simulation. A Ti-displacement-rotation region considered an intermediate structure during the domain formation was observed at the interfacial layer of the 5.5-min-annealing film. Because of the oxygen deficiency and the effect of ferroelectric domain modulation of the built-in barrier height, a good memristive behavior with a resistive switching ratio of 1916 was obtained in the 10-min-annealing BaTiO3 (BTO) film, offering an avenue toward the application of oxygen-deficient BTO in neural network applications.

François’ langur is an Endangered colobine inhabiting limestone habitats in southern China and northern Vietnam. Its global population has been estimated to be just more than 2000 mature individuals. Populations in Vietnam are highly fragmented with reportedly fewer than 200 adults in total and 50 in a single location. Although the François’ langur in Vietnam is highly imperiled as remnant populations persist in only three to four sites, little research has been carried out to provide a reliable estimate of its remaining population. In this study, we conducted field surveys in Lam Binh District, Tuyen Quang Province, northeastern Vietnam. In total, we recorded at least 16 groups of François’ langurs, with 156 individuals, raising the total number of individuals by approximately 10% compared to a previous study. The group structure, group size, activity budget, and density of the Lam Binh population resemble those reported in François’ langurs in China and other limestone langur species. The results show that the behavior ecology of limestone langurs significantly differs from that of forest langurs probably because they occupy separate habitats with distinctly different environmental variables. During our surveys, we detected a number of direct threats to this population, namely illegal logging, hunting, firewood collecting, hydropower development, grazing, and mining. It is recommended that the protection forest be elevated to the nature reserve status to better protect the most important population of the François’ langur in Vietnam.

Visible-light-induced generation of dithianyl and dioxolanyl radicals via selective hydrogen atom transfer (HAT) has been achieved. This radical relay tactic enables remote C(sp3)-H functionalization to permit rapid access to polyol and spiroketal segments, and in turn has been exploited as a key synthetic construct in the total synthesis of the danshenspiroketallactones. The conformational stability of the danshenspiroketallactones has also been defined via experiments and DFT calculations.

Alzheimer’s disease (AD) and Parkinson’s disease (PD) represent the most prevalent neurodegenerative disorders severely impacting life expectancy and quality of life of millions of people worldwide. AD and PD exhibit both a very distinct pathophysiological disease pattern. Intriguingly, recent researches, however, implicate that overlapping mechanisms may underlie AD and PD. In AD and PD, novel cell death mechanisms, encompassing parthanatos, netosis, lysosome-dependent cell death, senescence and ferroptosis, apparently rely on the production of reactive oxygen species, and seem to be modulated by the well-known, “old” second messenger cAMP. Signaling of cAMP via PKA and Epac promotes parthanatos and induces lysosomal cell death, while signaling of cAMP via PKA inhibits netosis and cellular senescence. Additionally, PKA protects against ferroptosis, whereas Epac1 promotes ferroptosis. Here we review the most recent insights into the overlapping mechanisms between AD and PD, with a special focus on cAMP signaling and the pharmacology of cAMP signaling pathways.

The current decline in global biodiversity is most evident in amphibians with 41% percent of all species worldwide classified as threatened with extinction. Hence, a major challenge in amphibian conservation is the high number of threatened species, leading to a common approach of identifying priority species and regions for conservation efforts. As a part of one of 36 globally designated biodiversity hotspots, Vietnam is considered to be of particular importance for conservation action. To improve amphibian conservation in Vietnam, this study provides an updated species list and assesses their threat status by compiling data from a variety of sources. Furthermore, a Zoological Information Management System (ZIMS) analysis was conducted to determine the representation of extant amphibians from Vietnam in zoos worldwide. The batrachofauna of Vietnam is characterized by a high level of species richness and local endemism as well as a high rate of new discoveries, with more than half of the endemic species reported exclusively from their type locality, making them especially vulnerable to extinction. Up to 18% of all amphibians extant in Vietnam and 28% of endemic species are classified as threatened with extinction by the IUCN. In many cases, the IUCN Red List status is either missing or outdated, highlighting the urgent need of action. Around 14% of endemic amphibian species have been recorded exclusively from unprotected areas, suggesting prioritization for further research and conservation measures. The continuing decline in many species remains an unresolved problem. As a guide for future research and conservation measures, a list of the top 57 species was compiled. In addition, according to the ZIMS analysis, only 8% of threatened and 3% of endemic amphibian taxa from Vietnam are currently kept in zoos worldwide, and a richness analysis revealed that the highest density of husbandries is found in Europe and North America. To achieve maximum outcome for the conservation of threatened species, this study recommends a general shift by zoos towards maintaining species in greater need of captive assurance populations and breeding programs to support integrative strategies that combine in situ and ex situ conservation efforts following the IUCN’s One Plan Approach.

Abstract Background In 2016, we conducted a systematic review to assess the feasibility of treatment monitoring for people living with HIV (PLHIV) receiving antiretroviral therapy (ART) in low and middle-income countries (LMICs), in line with the 90-90-90 treatment target. By 2020, global estimates suggest the 90-90-90 target, particularly the last 90, remains unattainable in many LMICs. This study aims to review the progress and identify needs for public health interventions to improve viral load monitoring and viral suppression for PLHIV in LMICs. Methods A literature search was conducted using an update of the initial search strategy developed for the 2016 review. Electronic databases (Medline and PubMed) were searched to identify relevant literature published in English between Dec 2015 and August 2021. The primary outcome was initial viral load (VL) monitoring (the proportion of PLHIV on ART and eligible for VL monitoring who received a VL test). Secondary outcomes included follow-up VL monitoring (the proportion of PLHIV who received a follow-up VL after an initial elevated VL test), confirmation of treatment failure (the proportion of PLHIV who had two consecutive elevated VL results) and switching treatment regimen rates (the proportion of PLHIV who switched treatment regimen after confirmation of treatment failure). Results The search strategy identified 1984 non-duplicate records, of which 34 studies were included in the review. Marked variations in initial VL monitoring coverage were reported across study settings/countries (range: 12–93% median: 74% IQR: 46–82%) and study populations (adults (range: 25–96%, median: 67% IQR: 50–84%), children, adolescents/young people (range: 2–94%, median: 72% IQR: 47–85%), and pregnant women (range: 32–82%, median: 57% IQR: 43–71%)). Community-based models reported higher VL monitoring (median: 85%, IQR: 82-88%) compared to decentralised care at primary health facility (median: 64%, IRQ: 48-82%). Suboptimal uptake of follow-up VL monitoring and low regimen switching rates were observed. Conclusions Substantial gaps in VL coverage across study settings and study populations were evident, with limited data availability outside of sub-Saharan Africa. Further research is needed to fill the data gaps. Development and implementation of innovative, community-based interventions are required to improve VL monitoring and address the “failure cascade” in PLHIV on ART who fail to achieve viral suppression.